PROJECT SUMMARY Allogeneic hematopoietic cell transplantation (HCT) is an essential therapeutic procedure used to enhance the outcome of patients with acute myeloid leukemia (AML) and myelodysplasia (MDS). Recent advances in alternative donor transplantation and supportive care have allowed for a greater number of older adults and those with co-morbidities to pursue potentially curative transplant procedures. In addition, the emerging era of targeted therapy allows for the development of novel disease remission induction regimens as well as transplant conditioning regimens that can enhance outcomes. However, relapse after allogeneic HCT remains a major barrier to successful outcomes, with recent data suggesting that up to 50% of allogeneic HCT failure and mortality relate to persistence or relapse of underlying disease. Recent advances in the detection of minimal residual disease (MRD) have enhanced the capacity of identifying some patients at risk of relapse after HCT. Using information obtained by cytogenetics, fluorescence in situ hybridization (FISH) and genomics, successful outcomes can still be achieved in a subset of myeloid malignancy patients transplanted in the setting of morphologically active or MRD-detectable disease at the time of transplant. This proposal is a pilot study to determine whether augmented genomic MRD assessment both before and after transplant for myeloid malignancies can be used to guide clinical investigators into offering post-HCT therapy. In so doing we hope to establish the importance of both pre- and post-HCT MRD and to begin to explore novel interventions for post-HCT MRD using a variety of cellular and/or pharmacologic-targeted approaches.